DE2209467A1 - DERIVATIVES OF 1-PHENOXY-3-AMINO-PROPAN2-OL AND PROCESS FOR THEIR PRODUCTION - Google Patents

Description

Derivatives of l-phenoxy-3-aminopropan-2-ol and process for their preparation

The invention relates to new, pharmacologically valuable Derivatives of l-phenoxy-3-ar.iino-propan-2-ol of the general Formula I.

- 0-CiI ₀ -CH-CH ₀ -OTI-X

ί ~ ι I Jw

where X = -CII = CH-C - (- || a or

-CH ₂ -CH ₂ -CII-J-j] b

OH

and the phenyl nucleus I is one, two or three times, in particular by alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, alkoxy, alkenyloxy, alkynyloxy, phenyl, halogen or the radical -NPb ₁ R ₀ , where R. is alkyl or acyl and R _{n is} hydrogen or alkyl], can be substituted, their aldehyde condensate products and acid addition salts sov / in Miro Hers fcel lurii; and usage »Die Sub.sti tuentrsi fh *; Phony I kerns I can equal oiler versoh i (mKmi .ioiru

BAD OR (GINAL

Ί 0 ^C J ij 0 7 / Tj ü 6

- 2 - 2200η67 nef. 2919

Compounds according to the invention with X = -CH ₂ -CH ₂ -CHOHJL jl are preferred.

The pyridyl radicals in the compounds according to the invention can be 2-, 3- or 4-pyridyl radicals.

In the context of the present invention are under the Compounds of the general formula I are also possible Stereoisomers and ptically active compounds and mixtures understood thereof, especially the racemate.

The substituents of the phenyl nucleus I have the following meanings in particular:

Alkyl with 1 to h carbon atoms, for example methyl, ethyl, propyl, tert-butyl;

Alkenyl with up to 6 carbon atoms, preferably vinyl, allyl, methallyl, crotyl;

Alkynyl with up to 6 carbon atoms, e.g. propargyl; Cycloalkyl with a ring size of 5 to 8 carbon atoms, preferably Cyclopentyl and cyclohexyl; Cycloalkenyl with a ring size of 5 to 8 carbon atoms, preferably cyclopentenyl;

Alkoxy, alkenyloxy and alkynyloxy each with up to 5 carbon atoms, preferably methoxy, ethoxy, propoxy, butoxy, Allyloxy, methailyloxy, propargyloxy; Halogen, preferably bromine or chlorine.

Alkyl radicals for It ₁ or R ₀ preferably have 1 to 2 carbon atoms.

BATH ORIGINAL

309807/1 306

Under the acyl residue for IU, the look is an aromatic one or aryl- or alkyl-substituted carbonyl radical derived from aliphatic carboxylic acid and having up to 11 carbon atoms understood, e.g., pormyl, acetyl, propionyl, butyryl, benzoyl, naphthoyl, phenylacetyl, preferably but acetyl or benzoyl.

The aldehyde condensation products of the compounds of the general formula I are oxazolidines of the formula Ic

O - CH

2 ^ n ^ - ^ j ^

those in the ¹ condensation of compounds of the general formula I with an aldehyde of the formula

R, - CHO ₁

in which R represents hydrogen or a lower alkyl radical with up to h carbon atoms are formed »

Inorganic and organic acids are suitable for forming salts with the compounds of general formula I. Suitable acids are, for example, hydrogen chloride, hydrogen bromide, phosphorus, sulfur, oxalic, milk, Tartaric, vinegar, salicylic, benzofic, citric or adipic acid. Pharmaceutically acceptable acid addition salts are preferred.

BATH ORIGINAL 309807/1306

Compounds of the general formula I can be prepared, for example, by the processes described below where the phenyl nuclei I of the following formulas, as above for the general formula I indicated, can be substituted.

Procedure A

A l-phenoxy-3-aminopropan-2-ol of the general formula II is combined with a compound of the general formula III a compound I according to the invention implemented:

(/ IVV _- O-CH ₀ -CH-CH ₀ -NH ₀ + YX * / 1 XV-O-

\ / I 'TrV \ /

\ = J _0H ni \ _ / _ÖH

II III I

Here, X has the meaning already mentioned and Y denotes halogen, in particular chlorine or bromine, and provided that X is -CH = CH-C-I- Ii, also -OH. -OK or-ONa.

Procedure B

A compound of the general formula IV becomes a compound according to the invention with a compound of the general formula V Compound I implemented:

// IVO-CH _n -Z + H ₂ NX> ^ iy- O -CH ₂ -CH-CH ₂ -NH-X

OH

IV

BATH ORIGINAL

309807/1 306

Here, X has the meaning already mentioned and Z means:

-CH - CH ₀ a or

-CH - CH ₀ -HaI

Hai stands for a halogen atom, in particular chlorine or Bromine"

Procedure C

Compounds of the general formula I according to the invention cores auoh by implementing a compound of general Formula VI can be synthesized with a phenol of the general formula VII.

/ 1 V-OH + Z-CH ₀ -NII-X - χ / l V- 0-CH ₀ -CH-CH _n -NH-X

ν = / \ w _0H

VII VI I

Z and X have the meanings already mentioned.

Procedure ^ D

The preferred compounds Ib according to the invention (X = -61I ₀ -CH ₀ -CIIOII-I- · in formula I) can furthermore also be prepared by hydrogenation of the compounds Ia according to the invention and of compounds of the general

30 S807 / 1306

ORIGINAL INSPIRED

Ref. 2919

Formulas VIII, IX or X are prepared;

O-Cn ₂ -CH-CH ₂ -NH-CH = CH-C
O

OH

Yes

/ l \ -0-CH ₀ -C-CH ₀ -NH-X £ ti <2

VIII

'1V-O-CH ₂ -C-CII ₂ -Nn-CH ₂ -CH ₂ - O

IX

<! IV-O-CH ₂ -Ch-CH ₂ -NH-CH ₂ -CH ₂ -C-Γ I.

ir

The individual processes and the production of the starting materials required to carry them out are described below explained in more detail:

The reaction according to process Λ is normally carried out in a suitable solvent or dispersant, in which the reactants are dissolved or suspended. Such solvents or dispersants are e.g. Benzene, toluene, acetone, dioxane. In particular, polar solvents such as alcohols are used as solvents. The reaction often takes place at normal temperature,

309807/1306

ORIGINAL INSPECTED

If X stands for -CH = CH-CO-- f Tird di- # Re.aiition through. Addition of acidic acid, preferably accelerated hydrogen chloride * Bfti Y = OH are sufficient btvn- its catalytic «- deficiencies in the acid, ζ" Β * of acetic or formic acid _e If Y = 'Ha or OK, then about 1 mole of the acid is added * Instead of this, the compound of the general formula TT · η can also be in the form of a salt psj ζ ,, Ε «. des Hyö rc & hal: g? t: A d ~ _t * ^; '^: £> * - -fi' - '■ be. If Y stands for halogen "data " k & t :: i the tertive. ^ 1- = r general formula III can also be used in the form of the hydrohalog-oil.

The pyridylpropenone compounds required as starting compounds the general formula IHa

Y-CH = CH-C-L IiI IHa

(X = CH = CH »C-nH I in formula III)

may be obtained ^ JBden raan the 2- or 3- ₉ "h- acetyl-pyridin under the Eediiigutiaen tir.?r alkaline Esterkondensation with a particular Amejsensäureester _f Ameisensäuremethyl- or -äthylestftr, reacting" Ατι "ü ^ n representable as sodium or * potassium salts of Tvtiyl! gen 2- _? 3- or ^! -Pyridine carboxylic acids can c «rc, h Hydr Iy-R-the vJnylog ^ n pyridinecarboxylic acids (Y = 0 ^π in formula I'Jlai

309807/1306 BAD original

- β - 2203467 Eef. 2919

which in turn are treated with suitable halogenating agents such as thionyl chloride or phosphorus tribromide into the corresponding vinylogous pyridine carbon- acid halides of the general formula HIb (Hai = halogen, in particular Cl or Br) can be converted

IHh

Compounds of the general formula IH, in which Y = halogen (Hal), in particular bromine or chlorine and X = -CH ₀ -CH ₀ -CHOH-Ii |) and which thus denotes the

general formula IHc applies

Hal-CH ₂ -CH ₂ -CH-I: j] IHc

Shark - CH = CH - C

CH

can from the corresponding compounds IHb by hydrogenation, expediently with complex hydrides, such as • lithium aluminum hydride, sodium borohydride or the like, are produced ·

The compounds of the general formula II required as starting compounds can be prepared by that a compound of the general formula IVa • IVb

309807/1306

Y 1 \ -0 "CH ₀ -CH -CH _0/1 \ -0-0H ₀ -CH-CH ₀ -HaI

IVa TVb

where in IVb Hal denotes an halogen atom, in particular chlorine or bromine, or a mixture of a compound IVa with a compound which is equally substituted in the phenyl nucleus I
IVh with ammonia or ammonia split-etide compounds
converts · ,, Dif reaction can under A ^ mosphärendruek od ^ r
under increased Dru "-lc b * i Umg? -bungs '' temperature durchg ^ iülirt and by supplying heat, for," B _& duroh Γ-rwärrafcfc to 70 G, accelerated or brought to completion _β

The compounds of the general formulas IVa uiiü TVb
ki'innen by reaction of a ^ s phenol of al
Forme L VIT

^0H

with an epihalohydrine expedient i \ m ise made with epihlorohydrin or epibromohydrin ^ performedi.? Depending on the reaction conditions, a v ^ rb: -i-formation arises
general formula Wa rwlt-r IVb or a (ri-nitsrh. von F ^ rbindunt '-' n ier al I ^ * 11 · ~ tnrn formulas IVa and ί.? ί _a Γ as »nt—
st.andenö Reakt ι c n> \ i t üul.t can for its further reaction with ammonia isolated v / ^ fieti, but it can also without
lM, left: M, ng can be implemented further directly »

BAD ORKSiNAL

3ÜS8 07 / 130S

When carrying out process B, a mixture of two compounds IVa and IVb can also be used, which are equally substituted in Phenylkera I. So get by reacting 3-amino-1- (pyridyl) -propan-lolen of the formula Vb with compounds of the general formulas IVa or IVb directly according to the invention of the general formula Ib:

0-CH ₀ -CH - CH + H ₀ N-CH ₀ -CH ₀ -CH

OH

3Va

Vb

-CH ₂ -CH-CH ₂ -IIaI +

IVb

0-CII ₂ -CH-CH ₂ -NH

! H-CH ₂ -CH ₂

Ib

Vb

The reactions according to process B are carried out in a suitable manner -Solvent at normal or elevated temperature carried out. Suitable solvents are e.g. benzene, toluene, acetone, dioxati, alcohols * The conversion of compounds of the general formula IVb can be in the presence of acid-binding agents, such as potash, soda, etc., or without acid-binding agents are carried out, being im in the latter case I usually receive the hydrohalides from Ib.

BATH ORIGINAL

309807/1306

22O £ 467 ^Rei · ²⁹¹⁹

B ^ i the method C can also be used instead of a uniform Compound of general formula VI, a mixture of e.g. VIa and VIb

₀ - CH ₀

- ²

CH - CH - NH - CII ₀ - CH

X ₀ /

Via

Hal-CH ₂ -CH-NH-CH ₂ -CH ₂ -CH OH OH

Vrb

with the same pyridyl radical used τ / earth * The Reactions according to process C can be carried out either in an aqueous alkaline solution, for example in dilute sodium hydroxide solution or in suitable solvents such as benzene, toluene, dioxane, but preferably in absolute acetone in 6 * can be made entirely of potash or soda * The reaction can be carried out at normal temperature or accelerated or completed by heating: β

h ά-m method D can be derived from the inventive Connections Ia

ff τ \ - 0-CH ₀ -Ch-CH ₀ -NH-CH = CH-C-f- X

OH O ^

Yes

309807/1306

by hydrogenation compounds Ib according to the invention

/ i VO-CH ₂ -CH-CH ₂ -Nh-CH ₂ -CH ₂ -CE- + II Ib
OH OH

be produced. Complex hydrides, such as, for example, lithium aluminum hydride, sodium borohydride and the like, are advantageously used for the hydrogenation. The reaction is carried out under the reaction conditions known for these hydrides, but only in an alcohol / water mixture in a room or at an elevated temperature, for example boiling on the soot. The hydrogenation can also be catalytic, for example under
If a palladium-carbon catalyst is used, it will be carried out.

In the same way, compounds of the general formulas VIII, IX w δ X can be hydrogenated. Starting compounds of the general formula VIII can be prepared by reacting a compound of the general formula XI with a compound

fj XO-CH ₂ -C-CH ₂ -NH ₂ + Hal-CH = CH-C-ρ jl

XI IHb

U I \ -O-CH ₂ -C-CH ₂ -NH-CH = CH

villa

309807/1 306

2 20; l 4 6 /

_# 2919

O
XI

+ 1IaI-CII ₂ -CII ₂ -CII OH

IIIc

I \> - 0-CH ₀ -C-CII ₀ -NII-CIi ₀ -CII ₀ -CH

VIIIb

of the general formula III!) or III0 can be obtained « In general notation, the implementation equation is

/ I VO-CH ₀ -C-CII ₀ -NH ₀ + Ilal-X

XI

IHd

0-CII ₀ -C-CII ₀ -MI-X

ff

VIII

where in the general formula IHd Hai halogen, preferably Means chlorine. The conversions between the VerMri-J / .ng «n of the general formula XI and IIIc or IHb are J21 solvents such as benzene, toluene, chloroform, methylene (Chloride, dioxane, etc. at normal or elevated temperatures ha ' in the presence of at least molar amounts of acid-binding agents * Agents, such as potash or soda, or in the absence of acid-binding agents, being carried out in the latter Usually obtained the Ilydrohalogenide of the compounds VIII.

ORIGINAL INSPECTED

7/1 3 Q 8

Ref. 2919

For the preparation of compounds of the general formula XI, for example, a phenol of the general formula VII is added a haloacetone of the general formula XII, e.g. bromooeton, um, brominated or chlorinated the product obtained of the general formula XIII, whereby a compound of general formula XIV arises, which can be converted into a compound with ammonia or ammonia-releasing compounds

general formula XI transferred.

I VOCH ₂ COCH ₃ .

XIII

/ l \ flH + HaICH ₂ COCH ₃

\ lx) CH ₂ COCH ₂ Hal

VII

XII

XIV

O-CH,

CH ₂ -HaI + NH ₃

XIV

V_ O-CH ₂ -C-CH ₂ -NH ₂

XI

Starting compounds of the general formula IX can by a Mannich reaction from a compound of the general Formula XI, formaldehyde and 2-, 3- and 4-acetylpyridine getting produced.

Compounds of the general formula X can be synthesized by a Mannich reaction from a compound of the general formula II, formaldehyde XV and a v2-, 3- or h- acetylpyridine of the general formula XVI:

ORIGINAL INSPECTED

3Ü9007 / 1 306

2202467

- 15 - »public 2919

-CH-CH ₀ -NH + CH ₀ O + CH, -C ι «s -> II OH 0

II XV XVI

■ Ah

Aldehyde condensation products of the formula Ic of the compounds according to the invention are obtained by adding compounds of the general formula I with -ineai aldehyde for the formula R, -CH0, where. IU hydrogen or a lower alkyl radical, meaning ¹ ', in a diluent or solvent, for example ethanol, preferably in the presence of an acidic catalyst, for example acetic acid or hydrochloric acid and preferably at elevated temperature a Sclij? -ρρ * - means, for example benzene, can be removed by azeotropic distillation or by means of a dehydrating agent such as anhydrous potassium carbonate.

The acid addition salts of the compounds of the general Formula I can be prepared from the components in a manner known per se. Here the application is one Diluents are generally advantageous, and in the case of an excess of acid, the di-salses are generally used of the compounds of general formula I is obtained. The mono-acid addition salts are obtained either by targeted Addition of only 1 mol of acid or by partial addition of the di-acid salt.

309807/1306

The compounds of the general formula I according to the invention, their Aldehydkondensationsprodulcte Ic and their pharmaceutically acceptable acid addition salts have valuable pharmaceutical properties. For example, they are suitable for the treatment or prophylaxis of heart diseases. In addition, some of them have very pronounced ß-adrenolytic properties. The invention Compounds can therefore be used as pharmaceutical preparations on their own, in mixtures with one another or in a mixture with pharmaceutically acceptable diluents or carriers. The pharmaceutical preparations can be in the form of e.g. tablets, capsules, aqueous or oily solutions or suspensions, emulsions, injectable aqueous or oily solutions or suspensions, dispersible powders or aerosol mixtures. Pharmaceutical preparations In addition to the compounds of the general formula I according to the invention, one or more others can also be used pharmaceutically active substances, for example sedatives such as Luminal, Mtfprobamat and chlorine- prominent vase dilators, such as glycerine trinitrate and Carbochronmn; Diuretics such as chlorothiazide; heart toning agents such as digitalis preparations; Hypotension agents such as rauwolfia alkaloids; Contain bronchodilators and sympathomimetic agents such as isoprenaline and ephedrine

309807V 1306

The preparation of the compounds of the invention is explained in more detail in the following examples. The compounds according to the invention are often not distillable Oils, so that in some cases no melting point is given. In all cases, however, is the specified Structure by molecular analysis and / or infrared or Nuclear magnetic resonance spectrum secured.

example 1

4.2 g of 1-amino-3- (o-allyloxyphenoxy) propan-2-ol hydrochloride

<y \\ - 0-CH _o -CH-CII _o -: TII _o »HO 1

^ "λ. oh 0-CH ₂ -CH = CH

are suspended in 33 ml of alcohol, then 2.8 g of the sodium salt of nicotinoyl vinyl alcohol

., -C-CH = CH-ONa

ΓΙ

added and the mixture stirred for 20 hours at room temperature. The suspension is suctioned off and the residue washed with alcohol. The filtrate together with the washing alcohol is concentrated in vacuo. There remains an oil that after becomes solid for a short time. The residue is worked through several times with water and then recrystallized from alcohol. The l-nicotinoylvinylamino-3- (o-

309807/1 306

_ ₁₈ _

alIy1oxyphenoxy) propan-2-ol

_{nef # 2919}

OH 0-CH ₂ -CH = CH ₂

M.p .: 98 ° C

Analysis: (C ₂₀ H ₂₂ N ₂ O ₄ )

Calculated: C 67.8 H 6.2 N 7.9 found: 67.7 6.4 8.1

Yield: 4.6 g = 81 $ of theory

The required sodium salt of nicotinoyl vinyl alcohol can be prepared as follows:

47 g of sodium methylate are dissolved in 340 ml of absolute benzene suspended, then a mixture of 74 g of ethyl formate and 100 g are slowly added with stirring at 10 ° C 3-Acetylpyridine is added dropwise and the mixture is then left at room temperature for 24 hours. Washed twice with absolute benzene, then twice with absolute alcohol and finally twice with ether. Man thus receives the sodium salt of nicotinoyl vinyl alcohol in a yield of 90% of theory.

If, instead of 3-acetylpyridine, 2- or 4- ^ aetylpyridine is used, the reaction with ethyl formate and sodium methylate is analogous to the one obtained

309307/1306

- 19 - Ref. 2919

Sodium salts of the vinylogous pyridine-2- or - ^ -carboxylic acid.

This requires 1-amino-3- (o-allyloxyphenoxy) -propan-2-ol can be made as follows:

60 g 1- (o-allyloxyphenoxy) -2,3-epoxy-propane

0-CH ₂ -CH = CH ₂

(prepared from o-allyloxyphenol and epichlorohydrin in the presence of Pottasch · in acetone) are dissolved in 600 ml methanol, 300 ml of liquid ammonia was added, and stirred for 3 hours in an autoclave at 7O ⁰ C. It is then concentrated, the residue is dissolved in benzene, extracted twice with dilute hydrochloric acid, the aqueous acidic phase is separated off, made alkaline, extracted three times with benzene and the combined benzene phases are concentrated. The solid residue is recrystallized once from benzene. This gives l-amino-3- (o-allyloxyphenoxy) propan-2-ol

0-CH-CH-CH ₀ -NH ₀

4h ²

O-CH ₂ -CH = CH ₂

in a yield of 67% of theory
Fp .: 89 ⁰ C.

309807/1 306

The base may in the usual manner with ethereal hydrochloric acid into the l-amino-3- (o-allyloxyphenoxy) -propan-2-ol hydrochloride, mp. 110 ⁰ C are transferred.

Example 2

4, (^ l-Nicotinoylvinylamino-3- (o-allyloxyphenoxy) propan-2-ol

λ— ^

Ch ₂ -CH-CH ₂ -NH-CH = CH-C

OH O

O-CH ₂ -CH = CH ₂

are dissolved in 45 ml of methanol and 12 ml of water, 2.5 g of sodium borohydride are added and the mixture is stirred at room temperature for 5 hours. ^{The mixture is then stirred at 70 °} C. for 8 hours with the addition of a further δ g of sodium borohydride in portions, the mixture is then concentrated in vacuo and the residue is taken up in 60 ml of water and 60 ml of chloroform, the chloroform phase is separated off and the aqueous solution is washed twice with chloroform extracted, the chloroform solution dried with sodium sulfate and concentrated in vacuo. The remaining oil is dissolved in dilute hydrochloric acid, the solution is extracted three times with benzene and then the acidic aqueous phase is made alkaline with soda and finally extracted three times with chloroform. The chloroform solution is washed with water, dried and concentrated in vacuo.

3098077 1 306

-21- 2203467 ^Ref 2919

The l- (3 * -ß-pyridyl-3 ^l -hydroxy-propylanino) -3- (o-allyloxyphenoxy) -propan-2-ol is obtained as a thick yellow oil.

0-CH ₀ -CH-CH ₀ -Nh-CII ₀ -CH ₀ -CH. OH OH

0-CH ₂ -CH = CH ₂

Analysis: ( ^c ₂ o ^H 26 ^N 2 ° 4 ^

calculated: C 67.0 H 7.3 N 7.8 0 17.9 found: 67.2 7.1 7.6 17.8 Yield: 3.8 g = 82 $ of theory

Example 3

6.8 g l-nicotinoylvinylamino ^ -io-ethoxyphenoxyJ-propan

sy

0-C ₂ H ₅

are dissolved in 40 ml of methanol and 10 ml of water, 3.9 g of sodium borohydride are added and the mixture is stirred at room temperature for 10 hours. ^{The mixture is then stirred at 70 °} C. for 6 hours with the addition of a further 5 g of sodium borohydride in portions, the mixture is then concentrated in vacuo and the residue is taken up in 50 ml of chloroform and 50 ml of water, the chloroform phase is separated off, and the water phase is extracted twice more with chloroform, then the combined chloroform extracts dried and in vacuo

309807/1306

constricted. The remaining oil is converted into the oxalate and the salt is recrystallized from alcohol / ether.

The l- (3 ^l -β-pyridyl-3'-hydroxypropylamino) -3- (o-ethoxyphenoxy) propan-2-ol-dioxalate is obtained in this way. Mp .: 133 ⁰ C dec. Analysis: (C.

Calculated: C, 52.5, H, 5.7, N, 5.3 found: 52.6, 5.9, 5.5

Exploiter 9 g = 86 $ of that.

_even The free base can be represented as follows:

3.4 g of l-nicotinoylethylamino-3- (o-ethoxyphenoxy) -propane-2-Ol _f , prepared from 3-acetylpyridine, l-amino-3- (oethoxyphenoxy) -propan-2-ol and formaldehyde according to Mannich, are dissolved in 15 ml of methanol and 15 ml l / ater and treated portionwise under stirring at room temperature over 3 hours with a total of 2 g of sodium borohydride and then the mixture was left at room temperature for 2h hours. The solution is concentrated, taken up with chloroform / water and the chloroform solution is worked up. The l- (3 ^ ^l -β-pyridyl-3 ^t -hydroxy-propylamino) -3- (o-ethoxyphenoxy) -propan-2-ol is obtained in this way

(Γ VO-CH ₂ -CH-CH ₂ -Nh-CH ₂ -CH ₂ -CH-T ^

Ah oh

0-C ₂ H ₅ in a yield of 78 $ of theory

309807/1306

Ref. 2919

Example 5

h _t h g 1-Amino-3- (p-tert-butylphenoxy) -propane-2-oil

I.
OH

are dissolved in 80 ml of ethyl acetate and 5 | 6 g anhydrous potash added. A mixture is slowly added to this mixture with cooling and stirring

/-vinyl
of 4.1 g of nicotinoyl chloride hydrochloride

CO-CH = CH-Cl

HCl

(manufactured! vinyl alcohols from the Natriumsaiz of Nicdtiney, the first * Ln * the hydrochloride of the free Nicotinoy! vinyl alcohols and then with thionyl chloride in the vinylogous Nicotinsäurechlör'id hydrochloride is converted with HCl gas.) ml in 50 Essigester and then stirred 2k Hours at room temperature. It is then filtered off with suction, the residue dissolved in water, made alkaline with sodium bicarbonate and the solution extracted again with ethyl acetate. The ethyl acetate extracts are concentrated in vacuo together with the original ethyl acetate filtrate. After repeated recrystallization from toluene, 1-nicotinoylvinylamino-3- (p-tert-butyl-phenoxy) -propan-2-ol is obtained.

309807/1306

(CH ₃ ) 3 ^-C - \ Vo-CH ₂ -CH-Cn ₂ -NH-CH = CH-C

^ = 'Oh ο

M.p. 97 ° C

Analyzes ( ^c ₂ i ^H 26 ^N 2 ° 3 ^

Calculated: C 71.2 H 7.3 N 7.9 Found 72.1 7.3 7.7 Yield: 5.8 g = $ 82 of theory

The l-Nicotinoylvinylamino-3- (p-tert.butyl-phenoxy) -propan-2-ol can as described in Example 2!, With sodium borohydride to l- (3 ^f -beta-pyridyl-3-hydroxy-propyl ⁰ amino) -3- (ptert, butyl-phenoxy) -propane-2-oil

) -CH ₂ -CH-CH ₂ -NH-CH ₂ -CH ₂ -CH _ ^^ OH OH

(Pp. Of the dioxalate 176 ⁰ C) are reduced.

Example 6

11.4 g sodium salt d & r vinylogous pyridine-4-carboxylic acid

CO-CH = CH-ONa

are with 16.5 g of l-amino-3- (o-ethoxyphenoxy) propan-2-ol hydrochloride

309807/1 306

2 2 O 9 Λ Β 7

- 25 - Ref. 2919

\ S_0-CH _o -CH-CH _o -NH _o «HCl

/ I

^0H

0-C ₂ H ₅

stirred in 120 ml of ethanol for 24 hours at room temperature. It is filtered off with suction, the residue is washed with ethanol, then the ethanol filtrate is concentrated in vacuo. It behind- remains an oil that solidifies after several hours. The product is washed several times with water, then off Recrystallized methanol / water. This gives the l- (isonicotinoylvinylamino «3— (o — ethoxyphenoxy) —propane— 2-01

0-CH ₀ -CH-CH ₀ -NH-Ch = CH-C

OH · If ,

0-C ₂ H ₅

Mp 69 ° C

Analysis: (C ₁₉ H

Calculated: C 66.6 H 6.4 N 8.2 found: 66.3 6.6 7 »9 Yield: 15 g = 66% of theory

Example 7

14.5 g of l- (isonicotinoylvinylamino) -3- (o-ethoxyphenoxy) propan-2-ol are dissolved in 130 ml of methanol, then 32 ml of water are added and the solution is added in portions with 8.1 g Sodium borohydride added. The mixture is then stirred for 6 hours at room temperature, then another 8.1 g of sodium boron

309807/1306

2209457

Ref. 2919

hydride was added and the mixture was heated at 70 ° C. for 6 hours. The residue is then concentrated in vacuo, dissolved in 40 ml of chloroform and 40 ml of water, the chloroform phase separated and extracted dys water phase again with chloroform. The combined chloroform extracts are dried and concentrated in vacuo. The remaining oil is dissolved in dilute hydrochloric acid, the solution is washed twice with benzene, the aqueous solution is made alkaline with sodium carbonate, extracted with chloroform and the chloroform solution is concentrated in vacuo. The remaining oil is dissolved in ethyl acetate and converted into the oxalate with an alcoholic oxalic acid solution. The initially greasy salt solidifies when heated with ethanol. After the oxalate has been converted into the free base, 1 «- (3 '- ^ - pyridyl-3 ^f -hydroxy-propylamino) -3- (o-ethoxyphenoxy) -propan-2-ol is obtained

O-CH _n -CH-CH ₂ -NH-CH ₂ -CH ₂ -CH

OH

as a crystalline product, mp: 92 ^° C

Analysis: (C ₁₉ H ₂₆ N ₂ O ₄ ) Calculated: C 65.9 H 7.5 found:. 65.6 7.5 expanded ": 9.9 g = 67 $ of that.

OH

N 8.1 8.1

309807/1 306

The same product is obtained if 1-amino-3- (o-ethoxyphenoxy) propan-2-ol

VO-CH ₂ -CH-CH ₂ -NH ₂

with! - / ^ pyridyl) -3-chloro-propan-l-ol

Cl-CH ₀ -CH ₀ -CH.
H

(represented by reduction before isonicotinoy! vinyl chloride) in absolute acetone and anhydrous potash.

Example 8

k _t k g l- (2 ^f -methoxy-4'-allyl-phenoxy) -2,3-epoxypropane

CH ₀ = CH-CH ₀ - tf% —0-CH ₀ -CH - CH ₀ \ / ** \ / "

X) CH ₃

(represented by heating eugenol with epichlorohydrin and potash in anhydrous benzene: K _{Λ o} 138-145 ° C)

ρ 0.0 mmi

are with 6 g of l- (ß-pyridyl) -3-amino-propan-l-ol

heated under reflux in 60 ml of alcohol for 8 hours. It is then concentrated in vacuo and the residue in dilute hydrochloric acid dissolved, the solution washed several times with benzene, with soda

309807/1 306

made alkaline and the alkaline solution extracted with chloroform. The chloroform extracts are concentrated in vacuo, the residue is dissolved in a little absolute dioxane, an insoluble part is filtered off and ethereal oxalic acid is added to the filtrate. An initially greasy precipitate falls, which solidifies when heated with absolute ethanol. The product is recrystallized several times from absolute ethanol. Is obtained as the l- (3 ^l -beta-pyridyl 3 ^t -hydroxy-propylamino) -3- ^(2-methoxy-l 4 ^t allyl-phenoxy) -propan-2-ol dioxalate.
Pp .: 132 ⁰ C dec.
Analysis: (C ₂₅ H ₃₂ N ₂ O ₁₂ )
calculated: C 54.3 H 5.8 N 5.1 found: 5 ^, 1 6.0 4.8 Yield: 4.8 g = kjfo d.Th.

The l- (ß-pyridyl) -3-aminopropan-1-ol required as the starting product can be made as follows:

The sodium salt of nicotinoyl vinyl alcohol is used

J-CH = CH-ONa

m ^ t benzylamine hydrochloride analogous to the procedure in Example 1 around, reduces the resulting N- (nicotinoylvinyl) -benzylamine

309807/1306

η ο, / et π - 29 - *. *. *. <* - 'η-ό ι Ref. 2919

rait sodium borohydride analogously to the procedure in example 2 and thus receives l- (ß-pyridyl) -3 ~ in 55% yield benzylamino-propane-1-oil

1-CH ₂ -CH ₂ -NH-CH ₂ - /

as an oily product that deals in the usual way with Hydrogen in the autoclave to give 1— (β-pyridyl) -3-aiainopropan-1-ol

Qi

H-CH ₂ -CH ₂ -NH ₂ IH

(viscous oil) can be debenzylated. Ii analogue l / let it down other compounds of the general formula V b can also be prepared.

The compounds listed in the table were prepared in accordance with Examples 1 to 8. In the Table means 2-Py is a 2-pyridyl radical:

Correspondingly, 3-Py means a 3-pyridyl radical and 4-Py a 4-pyridyl radical.

In the table below are compounds of the general formula

ff \ 0-CH ₂ -CH-NH-X

listed, where ( ¹ O _n and X have the meanings given in the table.

309807/1306

Ref. 2919

3-CH,

-CH = CH-CO-3-Py oil, not distillable

3-CH ₃

2-Cyclopentyl -CH = CH-CO-3-Py

-CH ₉ -CH "-CH0H-3-Py dioxalate

* * Mp. 156 ⁰ C (decomp.)

M.p. 110 ^w C

2-C ₆ H ₅

4-CH ₃ CO-NH-

2,6-Cl ₂

-CH "-CH _o -CH0H-3-Py dioxalate

^Λ Mp. 166 ° C (dec.)

-CH = CH-CO-3-Py M.p. 105 C.

-CH _o -CH _o -CH0H-3-Py dioxalate

* M.p. 151 C (decomp.)

-CH = CH-CO-3-Py Mp. 107 ° C (dec.)

-CH ₂ -CH ₂ -CH0H-3-Py oil, not distillable

-CH * CH-Ö0-3-Py M.p. 127 C.

-CH _o -CH _o -CH0H-3-Py dioxalate

* * Mp. 160 ° C (decomp.)

2-OC ₂ H ₅

4-OCH

3 ·

2-OCH.

2-OC ₂ H ₅

,1

-GH = CH-CO-3-Py

-CH = CH-CO-3-Py

-CH = CH-CO-3-Py

-CH = CH-CO-2-Py M.p. 92 ° C

M.p. 108 ^° C

-CH _o -CH "-CH0H-3-Py Dbxalat

Mp 139 ° C

Fp

M.p .: 88 ^U C

309807/1306

Ref. 2919

2-OC ₂ H ₅

2-0-CH ₂ -C = CH

2-0-CH ₂ -C = OH

2-cyclohexyl

3-N (CH,) ₍

CH ₀ -CH ₀ -CH ^ -Py OH

-CH = OH = C0-4-Py

-CH ₉ -CH ₀ -CH - ^ - Py OH

-CH-CH-CO-2-Py

-CH ₉ -CH ₀ -CN ^ -Py OH

-CH = CH-CO - ^ - Py

-CH ₂ -CH ₂ -CH- ^ i-Py OH

-CH = CH-C0-4-Py oil

oil

Dioxalate pp. 142 ° C oil
oil

Pp. 103 ° C

Dioxalate m.p. 16 ° C

oil

2-Cl

.CH.

-CH ₂ -CH ₂ -CH- ^ t-Py OH

-CH = CH-C0-3-Py

-CH ₂ -CH ₂ -CH-3-Py OH

-CH = CH-CO-2-Py

-CH ₂ -CH ₂ -CH-2-Py OH oil

Mp. 126 ° C. Pp. 96 ⁰ C

Mp 127 ° C

Dioxalate pp. 183 C

309807/1 306

-CH = CH-CO-3-Py

oil

OH

Dioxalate m.p. 158 ° C

-CH = CH-C0-2-Py

oil

CH ₂ -CH ₂ -CH-2-Py OH

Dioxalate m.p. 143 C

-CH = CH-C O-4-Py

Mp 138 ° C

¹ y

OI

CH ₂ -CH ₂ -CH - ^ - Py) H

Dioxalate m.p. 157 ° C

4-Cl
2-CH ₃ -CO-NH- -CH = CH-CO-4-Py

M.p. 97 ° C

4-Cl
2-CH ₃ -CO-NH- -CH ₂ -CH ₂ -CH - ^ - Py
OH

Dioxalate m.p. 149 C

2,3- (0CH ₃ ) ₂ -CH = CH-CO-3-Py

. oil

.CH ₂ -CH ₂ -CH-3-Py OH

Dioxalate m.p. 127 C

2 _f 6- (0CH ₃ ) ₂ -CH = CH-C0-3-Py

oil

2-CH = CH, -CH ₂ -CH ₂ -CH-3-Py OH

-CH = CH-CO-2-Py

-CH ₂ -CH ₂ -CH-2-Py OH

Dioxalate mp. 172 ⁰ C

oil

Dioxalate m.p. 118 ° C

309807/1 306

Ref. 2919

2-CH ₂ -CH CH-CH ₃ -CH = CH-CO - ^ - Py

M.p. 112 C

0 5 -CH ₂ -CH ₂ -CH - ^ - Py
OH

-CH = CH-CO - ^ - Py

Dioxalate m.p. 162 C

Mp. 112 C ^U

OH

Dioxalate m.p. 158 ° C

3-OCH, -CH = CH-C0-3-Py

-cn »CH-co-3-Py

oil

Mp 139 ° C

-CH = CH-C0-3-Py

M.p. 100 ° C

-CH ₂ -CH ₂ - (JH-3-Py
OH

M.p. 87 C.

2-CH ₂ -CH = CH ₂ -CH = CH-C0-3-Py

M.p. 91 C.

2-CH ₂ -CH = CH ₂ -Br, 2-Cl -CH ₂ -CH ₂ -CH-3-Py
OH

-CH ₂ = CH-CO-2-Py

-CH ₂ -CH ₂ -CH-2-Py
OH

Dioxalate m.p. 137 C

M.p. 119 C.

Dioxalate m.p. 16 ° C

4-Cl, 5-CH ₃ , 2-IC ₃ H ₇ -CH = CH-C0-2-Py

Mp. 123 C.

309807/1 306

Ref. 2919

4-Cl, 5-CH-, 2-iC H ₇ -CH ₂ -CH ₂ -CH-2-Py
OH Dioxalate
M.p. 179 C. - -CH = CH-C0-3-Py M.p. 82 ^° C It -CH ₂ -CH ₂ -CH-3-Py
OH Dioxalate
M.p. 154 C. 2— / -CH = CH-C0-4-Py oil -CH ₂ -CH ₂ -CH-4-Py
OH oil It -CH = CH-C0-4-Py oil 2-Br -CH ₀ -CH ₀ -CH-4-Py
OH Dioxalate
Mp 141 ° C It -CH = CH-C 0-2-Py oil 2-0-CH-CH = CH ₀
I. CH ₃

-CH ₂ -CH ₂ -CH-2-Py

oil

309807/1306

Claims (1)

Claims 1. Derivatives of l-Pheroxy ~ 3-ar.iino-propan-2-ol der general formula I. / Vx " OH wherein X = -CII = CII-C -] - || c. or -CII ₀ -CH, -GH jfjl and the phenyl nucleus I means one, two or three times by alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, alkoxy, AlL: enylo: iy, alkynyloxy, phenyl, halogen or the radical -NH 1 U ₀ , where R _{1 is alkyl} or acyl and R "are hydrogen or alkyl, their aldelium condensation products and acid addition salts. 2. Derivatives of l-phenoxy - ^ - anino-propane ^ -ols according to claim 1, characterized in that the phenyl nucleus I one, two or three times by alkyl with 1 his h carbon atoms, alkenyl and alkynyl in each case up to to 6 carbon atoms, cycloalkyl and cycloalkenyl with a ring size of 5 to 8 carbon atoms each, alkoxy, alkenyloxy or alkynyloxy each with up to 5 carbon atoms _s 309807/1306 ²²⁰⁹ ^ 7 _Bet . ₂₉₁₉ Phenyl, chlorine or bromine or the radical - ₁₂ where R _{1 is} substituted for alkyl with 1 to k carbon atoms or acyl with up to 11 carbon atoms and R ₁ for hydrogen or alkyl with up to k carbon atoms * 3. Derivatives of 1-phenoxy-3-aminopropan-2-ol according to claims 1 to 2, characterized in that that the phenyl nucleus I by vinyl, allyl, methallyl or is substituted by crotyl. k. Derivatives of l-phenoxy-3-aminopropan-2-ol according to claims 1 to 3, characterized in that j that the phenyl nucleus I is substituted by cyclopentenyl j is. j 5. Derivatives of l-phenoxy-3-aminopropan-2-ol according to ι $ claims 1 to 4, characterized in that t the phenyl nucleus I by cyclopentyl or cyclohexyl ' is substituted. ί 7. Derivatives of l-phenoxy-3-aminopropan-2-ol according to claims 1 to 6, characterized in that 309807/1306 6. Derivatives of l-phenoxy ^ -amino-propane ^ -ol according to » claims 1 to 5 »characterized in that, the phenyl nucleus I by methoxy, ethoxy, propoxy, Butoxy, allyloxy, methallyloxy, propargyloxy is substituted. - 37 - Ref. 2919 that the phenyl nucleus I is substituted by the radical - ^ g where R _{1 is} hydrogen, methyl, ethyl, acetyl, benzoyl and R "is methyl or ethyl. 8. Process for the preparation of compounds according to Claims 1 to 7, characterized in that a compound of the general formula II / l \ - 0-CH ₂ -CHOH-CH ₂ -NH ₂ II with a compound of the general formula III III where X is -CH = CH-CLT II or and Y stands for halogen and, if X -CH = CH- means, also stands for -OH, -OK, -ONa, is implemented. 9 · Method of making compounds according to claims 1 to 7, characterized in that a compound of the general formula V J 309807/1306 Ref. 2919 H ₂ H - XV with a compound of the general formula IV in which Z = -CH - CH ₂ a or = -CH-CH ₂ -HaI b OH for Hal = halogen, means is implemented. 10 · Process for the preparation of the compounds according to the claims 1 to 7 t characterized in that a phenol of the general formula VII VII with a compound of the general formula VI Z - CH ₂ - NH - X VI where Z = -CH. - CH ₀ or -CH-CH ₀ -HaI for Hai = halogen 309807/1306 and X = -CH ^{= CH} TO or mean is implemented. 11. Process for the preparation of compounds of the general my formula 0-CH ₂ -CH-CH ₂ -Nh-CH ₂ -CH ₂ -CH- ^ Jj O ^ - ^ Jj wherein the phenyl nucleus I as in claims 1 to 7 indicated, can be substituted, characterized in that a compound of the general formula / \ - 0-CH _o -CH-CH _o -NH-CH = CH-cJ1j1 Ia OH or or IV-O-CH ₂ -C-CH ₂ -NH-X 0 VIII or / l H "-CH-CH-NH-CH wherein X is T-CH = CH or -CH ₂ -CH ₂ -CHX stands, is hydrogenated. 309807/1308 12. Use of compounds according to the claims 1 to 7 as pharmaceutical agents " 13 · Pharmaceutical preparation, characterized by » that there is one or more compounds according to claims 1 to 7 together with a pharmaceutical Contains proper diluents or carriers. 14. Pharmaceutical preparation, characterized in that that it also contains one or more other pharmaceutically active substances 15. Pharmaceutical preparation, characterized in that that the further pharmaceutical substance or substances from vasodilators, hypotension agents, Sedatives, heart tonics, bronchodilators, and sympathomimetic agents is chosen. 309807/1 306